Pharmacokinetic Consultation Service Research Articles

Pediatric Antibiotic Stewardship: Optimization of Vancomycin Therapy Based on Individual Pharmacokinetics.

Vancomycin has been a first-line treatment for Gram-positive infections for decades. However, strategies for therapeutic drug monitoring (TDM) and dose-optimization in pediatrics remain controversial. In this study, we analyzed the impact of specific antibiotic stewardship interventions on efficacy and safety of vancomycin therapy. From September 2014 to May 2017, we conducted a prospective study to compare a control and a TDM intervention group in our tertiary care center. As part of an antibiotic stewardship program, we implemented internal guidelines on correct vancomycin dosing, TDM timing, as well as targeted trough level range and installed a pharmacokinetic (PK) consultation service to adapt vancomycin dosing to individually calculated PK parameters. As primary clinical outcomes, the percentage of patients with sustained therapeutic vancomycin trough levels and treatment days with therapeutic vancomycin trough levels, that is, 10-15 mg/L were analyzed. Secondary outcomes included nephrotoxicity, readmission rate and mortality. Median daily dose required to achieve therapeutic trough levels was examined. Clinical outcomes for 90 control patients were compared with outcomes for 19 patients guided by a PK consultation service. Percentage of patients with sustained therapeutic vancomycin trough levels increased from 17.8% to 94.7% (P < 0.001) and percentage of treatment days with therapeutic vancomycin trough levels increased from 18.4% (117/637) to 665% (155/233, P < 0.001). Readmission rate decreased from 24.4% to 5.3% (P = 0.07). No differences in nephrotoxicity or mortality rate were observed between groups. A median daily dose of 72 mg/kg/d was required to achieve therapeutic trough levels. Our data demonstrate that implementation of internal guidelines and a PK consultation service was associated with a profound improvement of vancomycin therapy and, therefore, patient safety.

Individualized Vancomycin Dosing with Therapeutic Drug Monitoring and Pharmacokinetic Consultation Service: A Large-Scale Retrospective Observational Study.

BackgroundTo date, outcome data with a large sample size and data regarding the clinical outcomes of pharmacokinetic-guided (PK) dosing of vancomycin are limited.AimWe evaluated the pharmacokinetic and clinical outcomes of a PK-guided dosing advisory program, pharmacokinetic consultation service (PKCS), in vancomycin treatment.MethodsWe investigated vancomycin therapeutic drug monitoring (TDM) and PKCS use through a retrospective review of patients who had serum vancomycin trough concentration data from October 2017 to November 2018. Among these patients, we selected non-critically ill adult patients satisfying our selection criteria to evaluate the effect of PKCS. Target trough attainment rate, time to target attainment, vancomycin-induced nephrotoxicity (VIN), vancomycin treatment failure rate, and duration of vancomycin therapy were compared between patients whose dosing was adjusted according to PKCS (PKCS group), and those whose dose was adjusted at the discretion of the attending physician (non-PKCS group).ResultsA total of 280 patients met the selection criteria for the VIN analysis (PKCS, n=134; non-PKCS, n=146). The incidence of VIN was similar between the two groups (PKCS, n=5; non-PKCS, n=5); however, the target attainment rate was higher in the PKCS group (75% vs 60%, P = 0.012). The time to target attainment was similar between the two groups. Further exclusions yielded 112 patients for the clinical outcome evaluation (PKCS, n=51; non-PKCS, n=61). The treatment failure rate was similar, and the duration of vancomycin therapy was longer in the PKCS group (12 vs 8 days, P = 0.008).ConclusionIn non-critically ill patients, an increase in target trough achieved by PKCS did not lead to decreased vancomycin treatment failures, shorter vancomycin treatment, or decreased nephrotoxicity in vancomycin treatment. Considering the excessive amount of effort currently put into vancomycin dosing and monitoring, more selective criteria for individualized pharmacokinetic-guided dosing needs to be applied.

A regional pharmacokinetic consultation service.

Clinical pharmacokinetics represents a way to ensure that a patient is receiving an optimal dose of a given drug for a specific indication. Pharmacokinetic consultation services have been implemented in many teaching hospitals and tertiary care facilities in the past. This project evaluated the feasibility of expanding the process to several community hospitals with one coordinator. Twenty-seven hospitals, members of the Ottawa Valley Regional Drug Information Service, were approached. Fifty-two pharmacists from 21 sites agreed to participate. Four modules were taught: basic principles, theophylline, aminoglycosides, and digoxin. Regular follow-up meetings were arranged so pharmacists from different hospitals could share their administrative and patient-specific problems and solutions. After two years, 16 departments have implemented a clinical pharmacokinetic service and monitor 82% of targeted drug levels. The pharmacists trained in clinical pharmacokinetics through the project recommended changes in the regimen in 45% of all their consultations. Eight-one percent of these were accepted and implemented by physicians. These results indicate that pharmacists from small community hospitals can be trained by one individual to provide clinical pharmacokinetic services with minimal supervision. It also shows that these hospitals have a need for such services.

Practical computer-assisted dosing for aminoglycoside antibiotics.

In principle, computer-assisted individualization of antibiotic dosing offers the prospect of better patient outcomes through improved dosing precision. In practice, however, the expertise in pharmacokinetics required to operate these programs has precluded their use by most physicians and pharmacists. We developed a computer program for individualization of dosing of aminoglycoside antibiotics under conditions in which access to experts in pharmacokinetics is impractical. The program is accurate, yet it requires less effort for data collection than previous drug dosing programs did. The program generates advice on a broad spectrum of topics, including dose adjustment, interpretation of measured drug concentrations in blood, and recommendations for monitoring drug concentrations. We tested its performance by prospectively comparing it with a clinical pharmacokinetic consultation service in a series of 78 consecutive patients. There were no differences in accuracy or bias in the prediction of drug concentrations. The rate of agreement between the program's dosing recommendations and those of the consultation service was 67 percent. This rate of agreement is typical of interexpert variation. In a stratified set of 24 of the 41 instances with significant disagreement regarding the recommended dose, experts ranked the program's recommendations as highly as those of the consultation service (95% confidence interval for difference in rank, -0.30 less than chi less than 0.47). The results suggest that expert systems can be coupled with pharmacokinetic dosing programs to deliver high-quality clinical recommendations for administration of antimicrobial agents.

Therapeutic Drug Monitoring Services at Kyushu University Hospital in Japan

Quantitative evaluation of the therapeutic drug monitoring services (TDMS) provided in Kyushu University Hospital from August 1981 to April 1989 was performed. Since 1982, the annual number of assay requests was about 4300-4400, but the annual number of clinical pharmacokinetic consultation services (CPCS) showed a tendency to increase. Antiepileptics were the drugs for which CPCS were most often performed (26.3 percent of the population given drugs for which TDMS was available); digoxin, lithium, and theophylline followed. Preparation of one consultation required 1.5-2.5 hours. Our TDMS team consists of eight members. In 1988, the average time per week spent for CPCS and TDMS was 8.2 and 11.3 hours per member, respectively. Thus, the number of pharmacists performing CPCS and TDMS was 1.2 and 1.7 full-time equivalents, respectively.

Usefulness of a Gentamicin Pharmacokinetics Service in Selected High-Risk Pediatric Patients

A pharmacokinetic consultation service was initiated in 1985 at Children's Hospital ofPittsburgh for individualizing aminoglycoside therapy. Charts of all patients receiving these antibiotics were reviewed for clinical and laboratory data, and pharmacokinetic (PK) profiles were generated. PK data from oncology and appendectomy patients receiving gentamicin were analyzed to document the usefulness of the service. One hundred eighty-six PK profiles were obtained for 79 oncology patients. On initial determination, 57% (45) had therapeutic levels, 39% (31) had subtherapeutic peaks, and 4% (3) had toxic levels. Subsequent PK data in 47 patients showed that therapeutic levels were achieved in 85% (40/47) with recommended dosage changes. In three of seven patients with persistent subtherapeutic levels, recommended dosage changes were not followed. In the remaining four patients, changes in the volume of distribution made readjustment necessary. In the appendectomy group, 105 profiles were generated for 84 patients. On initial evaluation, 60% (51) had therapeutic levels and 40% (33) had subtherapeutic levels; no follow-up was available in 23 patients in the latter group. Eighty percent (8/10) of patients with subtherapeutic levels on initial evaluation achieved therapeuticlevels with recommended dosages; dosage recommendations were not followed in two patients who remained subtherapeutic. In both groups 20% of the levels obtained were unusable due to poor collection technique or inaccurate time of collection or dosing; use of these levels would have led to incorrect dosage changes. Individualizing gentamicin regimens based on pharmacokinetic evaluations optimizes dosing regimens to achieve therapeutic concentrations in these high-risk populations.

Serum phenobarbital concentration predictions by a personal computer software system.

The ability of a personal computer software system to predict actual serum phenobarbital concentrations (SPC) in outpatients taking phenobarbital chronically was assessed by comparing actual with predicted SPC for accuracy, bias, and precision. Data for a four-year period were collected on patients at an outpatient clinic's pharmacokinetic consultation service. The study group included 50 adults and children with at least one SPC taken at a known time after dose administration. Input variables were weight, sex, height, age, concomitant drugs and diseases, phenobarbital dosage regimen, and the time and reported value of all SPC. Initially, SIMKIN (SIMulated KINetics) simulated dosing regimens on the basis of literature estimates of pharmacokinetic parameters; SPC were then estimated for these regimens and compared with actual values. One or two additional SPC were added to the input data and analyzed, and the predicted SPC compared with actual values. Although SIMKIN's accuracy and bias as measured by regression analysis and mean prediction error, respectively, were within clinically acceptable limits, the precision was not. However, these results are limited by the population studied. Patient compliance, concomitant phenytoin therapy, changes in phenobarbital pharmacokinetic parameters with chronic dosing, and disease interactions may significantly affect predictive ability. The clinical effects of these factors need to be evaluated to further improve predictions.

Compliance of neonatal nurse practitioners with gentamicin pharmacokinetic recommendations

The compliance of nurse practitioners in a neonatal intensive-care center with gentamicin dosage recommendations from a pharmacokinetic consultation service was determined. Medical and pharmacokinetic dosage data were collected retrospectively from the medical records and pharmacokinetic consultation records of eligible neonates as soon as they had completed gentamicin therapy. Neonates for whom pharmacokinetic dosage recommendations had been followed by each of four neonatal nurse practitioners (NNPs) were compared with neonates for whom recommendations had not been followed to identify patient characteristics that might have influenced NNP compliance with the recommendations. Each NNP also completed a questionnaire designed to elicit information about professional and behavioral characteristics that might be associated with compliance. Data were collected for a total of 98 neonates. Discriminant analysis revealed no significant differences between the two groups of neonates. Although the NNPs perceived themselves to be in high compliance with the pharmacokinetic recommendations, the actual group compliance rate was 43%. Neonatal nurse practitioners may require special education in the proper use of pharmacokinetic dosage recommendations even if they perceive themselves to be compliant with those recommendations.

Accuracy of serum gentamicin concentration predictions generated by a personal-computer software system

Predictions of serum gentamicin concentration and half-life, using a personal-computer software system (SIMKIN [simulated kinetics]), were compared for accuracy as increasing amounts of patient-specific data were supplied to the computer. Data for a two-year period were collected for patients of a hospital's pharmacokinetic consultation service; the study group included adults who had at least one serum concentration for which time of last gentamicin dose was recorded. Input variables were age, weight, height, sex, serum creatinine concentration, concomitant drugs and diseases, gentamicin dosage, time of infusion, dosing interval, number of doses on each regimen, and time and reported value of all serum gentamicin concentrations. Individualized dosing regimens were calculated on the basis of literature estimates, and half-life and serum concentrations were then estimated for these regimens and compared with actual values. One or two measured serum concentrations were then added to the input data. The computer-estimated half-lives (obtained from single-point or two-point analysis in different dosage intervals) were compared with the half-lives determined from actual serum concentration data. Gentamicin serum concentrations were similarly compared. The computer's ability to predict subsequent serum concentrations improved in sequence for literature-averaged prediction and single-point and multipoint analysis. Accuracy of predicting whether peak concentrations were therapeutic or subtherapeutic and whether trough concentrations were toxic also improved as more patient-specific data were input. SIMKIN appropriately evaluated demographic and laboratory data and adequately predicted gentamicin half-lives and serum concentrations.

Cost analysis of an aminoglycoside pharmacokinetic dosing program

A two-year retrospective study was conducted on the effects on hospital costs and charges of a pharmacy-based pharmacokinetic consultation service for aminoglycosides. In a 185-bed, acute-care hospital, the pharmacy department provided a pharmacokinetic consultation service for all patients for whom serum aminoglycoside assays were ordered by the physician. Patient charges and hospital costs were determined for the 98 patients for whom, over a two-year period, pharmacokinetic consultations were performed. The effects of service were measured in terms of changes in costs and charges for drug products and supplies, changes in personnel costs based on altered dosing intervals, and laboratory costs and charges. Because many of the patients in the study were elderly, the kinetics service was able to increase the dosing interval for 45 patients. This produced reduced patient charges for drug products of $6284.55 for the 98 patients. Drug-assay charges were $9734.20 for these patients, but much of this cost would have been incurred without the kinetic service. Overall, the kinetic service reduced the hospital costs $563.28. Drug-charge savings to the patient and hospital costs were reduced by this pharmacy-based pharmacokinetic consultation service.

Appropriateness of sampling times for therapeutic drug monitoring

Serum sampling for drug concentration was evaluated for usefulness in pharmacokinetic calculations and dosage adjustment. The prospective study included serum samples for 11 drugs in hospital inpatients during a four-week period. Appropriateness of sampling regarding (1) time of drug administration and (2) steady state was determined. Both of these evaluations were used in the final rankings of appropriateness of the samples with regard to ease of interpretation and clinical usefulness. Digoxin, theophylline, tobramycin, and phenytoin accounted for 81% of the 466 samples evaluated. Sampling time was recorded for 56% of all samples. Based on time of dose administration, 54% of samples were obtained at the recommended time; 38% of samples were obtained at steady state. Basic pharmacokinetic methods could be used to interpret 15% of samples, while 44% required complex pharmacokinetic methods, 34% required assumptions about sampling time versus dosing history, and 7% should not have been used in dosage adjustment. The majority of plasma drug samples required more than basic pharmacokinetic methods for evaluation. For assessment of therapeutic drug regimens by monitoring serum drug concentrations, sophisticated pharmacokinetic consultation services are needed.

A Concurrent Gentamicin Review Program with a Pharmacokinetic Consultation Service

A Concurrent Gentamicin Review Program with a Pharmacokinetic Consultation Service

National survey of pharmacokinetic consultation services

National survey of pharmacokinetic consultation services